Welcome to the Genome. Michael Yudell
is, that identifiable traits could be passed down from generation to generation—it was not until Mendel that science began to understand the mechanisms underlying the transmission of these traits. (4)
The journey from abstract notions of inheritance to the sequencing of the human genome abounds with stories of discoveries both great and small that led to where we are today. Science seldom progresses in a straight line. The genome was always there for us to find but took centuries to discover because knowledge and the technological application of that knowledge advance fitfully, revealing gradually more over time, and the social and cultural context that prioritizes different types of knowledge ebbs and flows with that time. Scientists have not always made the right choices. Even today, in what has been called the post‐genomic age, we are likely making assumptions about our genes that future generations look back on and ask, “How could they have thought that?” The trials and errors of science are part of what makes this process so interesting.
Several major building blocks of life had to be discovered to make possible our entry into the genomic world. First, scientists needed to determine what constitutes the hereditary material that passes from one generation to the next. Second, they needed to find out what constitutes the biochemical basis for the expression of this intergenerational legacy. This endeavor required the ability to take cells apart and analyze the chemical components from different parts of cells. Scientists then needed to determine the ways in which these chemicals, the building blocks of life, interacted, how they were structured, and how that structure influenced the hereditary process. Finally, technologies needed to be developed to use this information to improve human health, agriculture, and our understanding of our place in the history of life on Earth.
It took almost 150 years from the discovery of the hereditary principles to the sequencing of the human genome. The stories behind these discoveries explain how scientists came to understand the biological basis of heredity. What follows does not represent the comprehensive history of all the important genetic work of the past century or so. Yet without the discoveries we highlight, the discovery of the genome would never have occurred or would have happened very differently.
The meanings and mechanisms of heredity were pondered and debated millennia before the development of modern genetics. In the fifth century BCE, the Greek dramatist Euripides wrestled with the complexities of the relationship between parent and child in his play Electra:
I oft have seen,
One of no worth a noble father shame,
And from vile parents worthy children spring, Meanness oft groveling in the rich man’s mind, And oft exalted spirits in the poor. (5)
Without knowledge of genes or genomes, premodern thinkers had many ideas concerning the nature of heredity, some of which were surprisingly sophisticated and accurate. To Euripides heredity must have been a mystifying and seemingly random process. How else could he and his contemporaries explain the inconsistencies among inherited traits within families? Other ancients carefully considered similar questions. Lucretius, a Roman philosopher, wrote that traits could skip generations, as children sometimes resembled their grandparents. (6) Around the globe, premodern farmers had already developed sophisticated breeding techniques that depended, in part, on a basic understanding of heredity. We know, for example, that the ancient Assyrians and Babylonians artificially pollinated date palm trees and that many animals, including sheep, camels, and horses were domesticated during ancient times. (7) The domestication and breeding of plants and animals shows that many early thinkers recognized that traits were passed between generations.
Perhaps the most advanced premodern thinker on heredity was Aristotle (384–322 BCE). (8) Aristotle dedicated much of his work to questions concerning the specific mechanisms of heredity. He theorized that inherited traits were passed between generations by what he called the eidos, or the blueprint, that gave form to a developing organism. Aristotle’s eidos was entirely theoretical—he could not see this invisible configuration—a fact that makes his theory all the more remarkable. Aristotle understood the mechanisms of heredity only in the broadest sense and remained handicapped by the limited technology of his time, a primitive understanding of biology, and the cultural limitations of his worldview. Yet a keen perception, buttressed by his emphasis on observation and description, made him a brilliant interpreter of the natural world.
The concept of the eidos remained the most complete theory of heredity until the modern era of genetics. More than two millennia later scientists use a genetic language strikingly similar to Aristotle’s. The eidos is in many ways analogous to the modern concept of a genome, and like Aristotle today’s scientists often refer to a genome as a blueprint for life. (9)
IN THE ABBEY GARDEN
For close to two millennia few scientists approached Aristotle’s understanding of heredity, though other theories were put forth during the centuries. Some, like the idea of the homunculus—the belief that every being was miniaturized and preformed in a reproductive cell—or the belief in panspermia—the idea that secretions from the entire body contribute to offspring—held sway for varying lengths of time. (10)
But before the late eighteenth century, ideas about what we today understand as heredity were quite different than our modern concept. Although similarities were recognized between parents and offspring and among families, such similarities, in a pre‐hereditarian worldview, were not generated by a hereditary mechanism, but by the act of conception itself, the pregnancy that followed, the development of the embryo, the birth, and, finally, lactation. There could be no laws of heredity in a system that viewed each creation of plant and animal life as isolated events. (11)
However, beginning in the eighteenth century, disparate fields of thought concerning hereditary phenomena would begin to converge on the road to developing hereditary theories. (12) Medical science, for example, began to systematically characterize disease. The taxonomic language of natural history moved toward uniformity. Professional animal and plant breeders more actively sought to breed specific features. Scientists investigated preformationist theories. And anthropology, in seeking to understand physical differences between peoples and populations, investigated the origins of human diversity. (13) From these various scientific investigations would slowly emerge both a popular and scientific discourse that would, over time, shape emerging concepts of heredity.
The work of Austrian monk Gregor Mendel, who bred peas in his abbey garden, built upon these growing discussions of heredity, and is credited with making the jump to studying heredity experimentally. But Mendel was not just a monk tending peas. The child of peasant farmers, he was a classically trained scientist raised in the greatest traditions of the Enlightenment. Intellectually nurtured by his family and schooled in the best academies and universities of Central Europe, the German‐speaking Mendel spent his life dividing his affection between God and science. (14) In 1843, at the age of 21, Mendel entered the St. Thomas Monastery in Brünn in what is now the Czech Republic. (15)
In the Church Mendel found a community of scientists—botanists, zoologists, and geologists among them—working diligently in their fields and making important contributions to the scientific literature. Perhaps the most important event in Mendel’s early career occurred 10 years into his stay at St. Thomas. In 1851, at the behest of his abbot, Mendel was sent to Vienna University to study at the institute of Professor Christian Doppler, one of the pioneers of modern physics. For 2 years at Doppler’s institute Mendel honed his scientific skills, taking courses in physics, chemistry, and mathematics, as well as entomology, botany, and plant physiology. The influence of physics was important to Mendel’s later work on heredity. Physics taught Mendel that laws governed the natural world and that these laws could be uncovered through experimentation. (16) But it was ultimately Mendel’s exposure to ongoing debates in heredity that transformed him into the scientist we remember today.
Mendel and his predecessors understood that traits could be passed between generations. A child with his mother’s eyes and his father’s nose was easy evidence of that. Breeding experiments with domesticated animals also suggested that traits were passed to offspring.
The prevailing theory during